Synthesis of 1-aminoalkylphosphinic acids. Part 2. An alkylation approach

Abstract

Aminomethylphosphinic acid (7), protected at nitrogen as the imine derived from benzophenone and at phosphorus as the diethylacetal and ethyl ester [i.e. (6)], undergoes facile LDA-induced alkylation. Treatment with primary alkyl halides affords, on product hydrolysis, a versatile route to phosphinic analogues of α-amino carboxylic acids. Analogues of alanine, valine, leucine, phenylalanine, tyrosine, histidine, and aspartic and glutamic acids are thus prepared; the phosphonic histidine analogue (23b) can be prepared similarly from the imine phosphonate diester (21). Intra- and inter-molecular dialkylation reactions provide analogues of 1-aminocyclopropanecarboxylic acid (14) and 2,6-diaminoheptanedioic acid (16). Benzyl bromide alkylation of (25a) and (30a), where the nitrogen is protected as the imine of the 2-hydroxypinan-3-one chiral auxiliary (24) or (29), is diastereospecific leading to asymmetric synthesis of either (+)- or (–)-phenylalanine analogues; this selectivity is compared to that shown by the corresponding chiral imine phosphonate (25b) and imine carboxylate (25c).